PROJECT SUMMARY/ABSTRACT This application describes two programs of research aimed at improving the efficiency and selectivity of chemical synthesis relevant to small molecule drug discovery efforts. The first program seeks to invent biomi- metic cascade reactions used by Nature to construct complex polycyclic terpenes and steroids many of which have profound biological activities. The second program seeks to invent stereodefined and functional building blocks that can be used to optimize therapeutic properties of small molecules at various stages of drug discov- ery and development efforts. The primary objective of the first program is to identify a new catalytic system that can initiate a cascade of ring forming reactions from polyunsaturated precursors. Nature constructs all terpenoids by initiating cationic cascade cyclizations under exquisite control of stereochemistry through either protonation or ionization of reac- tive groups (phosphates, epoxides). Chemical analogs of this natural process that have the same ability to cre- ate polycyclic systems with high levels of stereocontrol have only recently emerged. However, they are limited in their ability to introduce the requisite functionality needed for the production of the final product. By harness- ing the potential of chiral Lewis base catalysis, this program seeks to create enantiomerically enriched thiirani- um ions which will enable the initiation of the cationic cascade by spontaneously engaging the proximal double bonds in the substrate. The resulting polycyclic product will thus contain a thioether functional group at a stra- tegically crucial position that will allow subsequent manipulations into oxygen and carbon containing moieties. Further extensions of this sulfenium ion initiated cyclization strategy target the construction of biologically ac- tive spiroacetals and glycosides. The primary objective of second program is the creation of a small library of stereodefined, functionalized, three-dimensional building blocks that can be introduced as plugins for the optimization and diversification of small molecule candidates in drug discovery programs. One of the major problems facing the research and discovery efforts in the pharmaceutical industry is the mismatch between the chemical characteristics of avail- able screening libraries and the kinds of characteristics needed to intervene by association and interaction with biomolecular targets. This problem arises from the lack of robust methods that reliably and predictably install three dimensional carbon centers bearing appropriate functionality (oxygen, nitrogen) in both manual and au- tomated platforms. By systematic examination of the stereochemical outcome of the coupling of small, ste- reodefined boron-containing building blocks and a rigorous understanding of the mechanisms of their introduction, this program will provide the medicinal chemistry community with reagents that constitute ?stereo- centers in a bottle?; namely off the shelf plugins to accelerate discovery programs. The potential impact on pro- cess research enterprises is also significant by eliminating troublesome byproducts.